ABSTRACT The greatest hope for an end to the COVID19 pandemic caused by SARS-CoV-2 is a vaccine and/or antibody therapy. At this point, we know little about protective immunity to SARS-CoV-2, including which epitopes are the major target of the antibody response to this virus and whether antibodies to specific epitopes impact outcome. Advancing our understanding of SARS-CoV-2 immunity is critical not only for informing vaccine design, but also for understanding the epidemiology and spread of SARS-CoV-2, including among asymptomatic individuals. There is considerable focus on targeting the region of the Spike protein that interacts with the receptor, which has also been a focus of HIV vaccine efforts for more than three decades with limited success to-date. Thus, given the urgency due to this pandemic, multiple approaches are warranted to complement this approach. We propose comprehensive profiling of the antibody response to SARS-CoV-2, which has the potential to detect both neutralizing and non-neutralizing antibody responses to all the proteins in the virus. For this purpose, we will develop novel methods based on creating custom Coronavirus (CoV) phage display peptide libraries and using immunoprecipitation and deep sequencing to comprehensively examine the antibody response to SARS-CoV-2 in a high-throughput manner. Using this platform, we will develop and test custom libraries that encode all seven CoV clades, including genetic circulating variants and peptides spanning all viral proteins. This method will allow us to simultaneously detect antibodies to all CoVs in a person?s plasma, enabling the detection of the specific responses to SARS CoV-2 infection as well as providing insights on any interactions between common CoV and SARS-CoV-2 infections, be they protective or enhancing. We will also develop libraries of SARS-CoV-2 proteins that have mutations to all possible amino acids at every possible amino acid using an approach we pioneered called Phage-DMS. We have validated Phage-DMS as a tool to define key amino acids residues of epitopes and pathways of escape from antibodies. We propose to collect and compare convalescent plasma from verified cases of SARS-CoV-2, including those with severe symptoms, moderate symptoms and very mild symptoms as well as uninfected controls. The information gained from these studies will help identify the peptide sequences that define the epitopes targeted by antibodies in response to SARS-CoV-2 infection and those that distinguish SARS-CoV-2 infection from other CoV infections. We also hope to identify the antibody responses across the entire CoV genomes that correlate with outcome, including specific responses to SARS-CoV-2 as well as any interacting effects of responses to other CoVs.